Abstract: PO1633
RhoA-Rac1-CDC42 Regulators as Candidates for Monogenic Nephrotic Syndrome
Session Information
- Genetic Diseases of the Kidneys: Non-Cystic - 2
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Halawi, Abdul A., Department of Pediatrics, Boston Children's Hospital, HMS, Boston, Massachusetts, United States
- Deutsch, Konstantin, Department of Pediatrics, Boston Children's Hospital, HMS, Boston, Massachusetts, United States
- Schneider, Ronen, Department of Pediatrics, Boston Children's Hospital, HMS, Boston, Massachusetts, United States
- Klambt, Verena, Department of Pediatrics, Boston Children's Hospital, HMS, Boston, Massachusetts, United States
- Buerger, Florian, Department of Pediatrics, Boston Children's Hospital, HMS, Boston, Massachusetts, United States
- Onuchic-Whitford, Ana C., Department of Pediatrics, Boston Children's Hospital, HMS, Boston, Massachusetts, United States
- Zahoor, Muhammad Y., Department of Pediatrics, Boston Children's Hospital, HMS, Boston, Massachusetts, United States
- Bockenhauer, Detlef, Department of Renal Medicine, University College London and Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK, London, United Kingdom
- Shril, Shirlee, Department of Pediatrics, Boston Children's Hospital, HMS, Boston, Massachusetts, United States
- Hildebrandt, Friedhelm, Department of Pediatrics, Boston Children's Hospital, HMS, Boston, Massachusetts, United States
Background
Steroid resistant nephrotic syndrome (SRNS) frequently causes chronic kidney disease in children. 58 monogenic SRNS genes are known to cause 11%-29.5% of SRNS in children. These genes map to 12 distinct pathogenic pathways, including RhoA-Rac1-CDC42 regulators (RRCR). Genetic data indicate that many additional monogenic SRNS genes exist.
Methods
To search for additional monogenic SRNS genes, we generated two lists of independent functional candidate genes: i) 123 genes involved in the RRCR pathway, which has been implicated in the pathogenesis of nephrotic syndrome (Nat Commun 9:1960, 2018), and ii) 30 genes from a single-cell RNA sequencing (scRNA-seq) dataset (JASN 29:2060, 2018).
Results
First, we validated the candidate status of both candidate lists by overlapping them with the 58 known SRNS genes. 12 of the 123 RRCR candidates from list i) (9.7%) overlapped with the 58 known SRNS gene lists (20.6%). Likewise, of the 30 genes from list ii) that were most strongly expressed in podocytes (scRNA-seq), 9 overlapped (30%) with the 58 known SRNS genes (15.5%), thereby validating both functional candidate lists as relevant for SRNS pathogenesis. We then evaluated for overlap of both candidate gene lists [list i) RRCR and list ii) scRNA-seq] with 114 candidate genes that we identified by whole exome sequencing (WES) in 1,382 families.
We found that 10 RRCR candidates (8.1%) overlapped with the 114 WES candidates (8.7%). Interestingly, 2 genes (ARHGEF17 and MYO9A) overlapped with all three candidate gene lists, i.e. the 123 RRCR candidates, the 30 scRNA-seq candidates, and the 114 WES candidates. Within the 8 (of 10) remaining candidates the strongest mutation was detected in the NEK3 gene (NIMA Related Kinase 3). By WES we had identified a homozygous truncating mutation, p.N209Kfs*21, in a family of two siblings. We present data on the cell biological role of NEK3 in podocytes.
Conclusion
Utilizing two independent non-overlapping candidate lists, we established 10 potential novel candidate genes for human SRNS.